The overall objective of this research was to use a defined in vitro experimental system to study the molecular basis of quantitative control of gene expression and to investigate the relationship between phenotypic variability and neoplastic progression. Techniques were developed for detecting and quantitating, on a single cell basis, serum albumin and other specific antigens in hepatoma cells and normal hepatocytes, as well as specific surface antigens on normal and neoplastic human breast epithelial cells. The range of single cell variation in albumin content for normal hepatocytes and hepatoma cells and in specific breast antigen content for normal and neoplastic breast epithelial cells was at least 10-fold. This wide range of single cell heterogeneity was generated very rapidly in clonal colonies of less than 30 cells. By tests for periodicity using Fourier transform analysis, the single cell quantitative variation in both liver and breast cells was not random, but occurred in a quantal fashion within a square root of 2 geometric series (geometric phenotypic variability). The fit to this geometric series was best for normal cells. The rate of phenotypic variability was found to be indirectly proportional to the magnitude of the quantal shift and could be as high as 0.3 per cell per generation. The rate of phenotypic variability in hepatoma cells could be significantly manipulated (increased or decreased by as much as 4-fold) with dimethylsulfoxide, tumor promoters, and glucocorticoids. Human breast carcinoma cells had a 10-fold higher rate of phenotypic variability than normal breast epithelial cells. Breast cells from normal tissue peripheral to a breast carcinoma had a 3-fold higher rate than normal breast epithelial cells. In situ hybridization experiments with an albumin cDNA suggested a wide single cell variability in albumin mRNA. By analyzing the variability in albumin content of sister hepatoma cells, a model for geometric phenotypic variability (quantitative shift model) was developed that could explain several aspects of the clonal variability and phenotypic drift that is observed so frequently in tumors and cultured cells. (G)